Triple Drug Therapy for Advanced Melanoma

Recruiting at 250 trial locations

Overseen By Pfizer CT.gov Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Pfizer

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Immunodeficiency, Autoimmune, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 24 months

256 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a combination of three drugs to treat advanced skin cancer in patients with a specific genetic mutation. One drug helps the immune system fight cancer, while the other two stop cancer cells from growing. The study aims to see if this combination is safe and effective.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are using drugs that are known moderate or strong CYP3A4 inhibitors, you may need to stop them during certain periods of the study.

Is the triple drug therapy for advanced melanoma safe for humans?

Pembrolizumab, part of the triple drug therapy, is generally well tolerated with common side effects like fatigue, rash, and diarrhea, and less common ones like thyroid issues and lung inflammation. Encorafenib and binimetinib, also part of the therapy, have been associated with serious eye problems, skin issues, and heart-related side effects, but managing these can help patients stay on treatment longer. ^{1 2 3 4 5}

What makes the triple drug therapy for advanced melanoma unique?

The triple drug therapy for advanced melanoma combines BRAF and MEK inhibitors (encorafenib and binimetinib) with an immune checkpoint inhibitor (pembrolizumab), potentially offering improved efficacy and durability of response compared to standard BRAF/MEK inhibitor combinations alone, while also aiming to reduce certain side effects like fever and photosensitivity. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination used in the Triple Drug Therapy for Advanced Melanoma?

The combination of encorafenib and binimetinib has shown improved survival rates in patients with advanced melanoma, achieving a median overall survival of 33.6 months, which is longer than other similar drug combinations. Additionally, pembrolizumab, another component of the therapy, has been proven to be more effective than ipilimumab in treating advanced melanoma. ^{2 7 8 11 12}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

Adults with advanced or metastatic melanoma that has a specific BRAF gene mutation and no prior treatment for their condition. They must be able to follow the study plan, have at least one measurable lesion, proper organ function, and an ECOG status of 0 or 1. Exclusions include significant heart disease history, recent serious blood clots or strokes, active infections requiring treatment, brain metastases involvement, certain medication use within specified timeframes before the trial starts.

Inclusion Criteria

You have at least one detectable abnormality that can be seen on a scan or in a photo according to certain guidelines.

My melanoma has a BRAF V600 mutation confirmed by a certified test.

I haven't had systemic therapy for advanced melanoma.

Exclusion Criteria

You have signs of hepatitis B or C virus infection.

Pregnant, confirmed by a positive β-hCG laboratory test result, or is breastfeeding (lactating)

I haven't had any cancer except for certain skin, prostate, or cervical pre-cancers in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Open-label safety lead-in phase to determine the safety recommended Phase 3 dose and pharmacokinetics of encorafenib and binimetinib plus pembrolizumab combination therapy

6 weeks

Regular visits at the study clinic

Treatment

Participants receive pembrolizumab every 3 weeks, with half also taking encorafenib and binimetinib daily at home

Up to 24 months

Every 3 weeks for pembrolizumab infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib
• Pembrolizumab

Trial Overview The trial is testing a combination of three drugs: Encorafenib and Binimetinib taken orally daily at home along with Pembrolizumab given via IV every three weeks in the clinic. The goal is to assess their effectiveness when used together against melanoma that hasn't been treated before.

How Is the Trial Designed?

Group I: Triplet Arm Experimental Treatment 3 Interventions

Encorafenib and Binimetinib in combination with Pembrolizumab

Group II: Control Arm Active Control 1 Intervention

Pembrolizumab

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

The combination of encorafenib (ENC) and binimetinib (BIN) was found to be cost-effective compared to cobimetinib (COB) and vemurafenib (VEM) only at a very high willingness-to-pay threshold of $573,000 per quality-adjusted life year (QALY).

The combination of dabrafenib (DAB) and trametinib (TRA) was determined to be the most optimal treatment option for BRAF-mutated advanced melanoma, dominating the COB + VEM combination in terms of cost-effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. Halloush, S., Alkhatib, NS., Almutairi, AR., et al.[2023]

Binimetinib, an uncompetitive inhibitor of MEK1/2, has shown significant efficacy in treating metastatic melanoma, particularly in combination with encorafenib, resulting in a progression-free survival (PFS) of 14.9 months compared to 7.3 months with vemurafenib alone in Phase 3 trials.

While binimetinib has a tolerable safety profile, there is currently no long-term data on durable responses or overall survival benefits compared to other treatments, highlighting the need for individualized treatment plans for patients with BRAF-mutated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. Tran, B., Cohen, MS.[2021]

The combination of encorafenib and binimetinib has shown a median overall survival of 33.6 months in patients with advanced BRAFV600 mutation-positive melanoma, outperforming other BRAF/MEK inhibitor combinations that achieved 22 months.

Encorafenib's unique pharmacokinetics allow for prolonged binding and greater BRAF inhibition, which may lead to improved efficacy and better tolerability, with fewer side effects like pyrexia and photosensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. Trojaniello, C., Festino, L., Vanella, V., et al.[2019]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Encorafenib and binimetinib, a combination of a BRAF inhibitor and a MEK inhibitor, received FDA approval in June 2018 for treating patients with unresectable or metastatic melanoma that has specific BRAF mutations (V600E or V600K).

The combination therapy is also being explored in ongoing phase III clinical trials for metastatic colorectal cancer, indicating its potential broader application beyond melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. Shirley, M.[2019]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

The combination of encorafenib and binimetinib is now the standard treatment for patients with advanced melanoma harboring BRAF V600 mutations, based on the phase III COLUMBUS study.

While this combination therapy is effective, it is associated with specific adverse events such as serious retinopathy and cardiovascular toxicities, highlighting the importance of proactive management to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. Augustyn, K., Joseph, J., Patel, AB., et al.[2023]

In a 5-year study of patients with advanced BRAF V600-mutant melanoma, those treated with the combination of encorafenib and binimetinib (COMBO group) had a longer duration of survival without disease progression compared to those receiving either encorafenib alone or vemurafenib.

The combination treatment also resulted in fewer patients needing additional anticancer therapies after treatment, and while side effects were similar across all groups, they decreased over time for the COMBO group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF. Dummer, R., Flaherty, KT., Robert, C., et al.[2023]

The combination of encorafenib and binimetinib for treating BRAF-mutant advanced melanoma shows similar efficacy to existing treatments like dabrafenib+trametinib and vemurafenib+cobimetinib, based on clinical trial results.

This new combination has a lower incidence of certain side effects, such as pyrexia and photosensitivity, which can significantly improve the quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-term efficacy of encorafenib plus binimetinib combined treatment: case report.] Spagnolo, F.[2021]

Combination treatments of BRAF and MEK inhibitors, specifically vemurafenib + cobimetinib, dabrafenib + trametinib, and encorafenib + binimetinib, are the standard care for patients with BRAF V600-mutant metastatic melanoma, showing similar clinical efficacy across the board.

Each combination has unique safety profiles, with specific side effects such as fever with dabrafenib + trametinib, photosensitivity with vemurafenib + cobimetinib, and gastrointestinal issues with encorafenib + binimetinib, influencing treatment choices based on patient tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment combinations in BRAF-mutant metastatic melanoma.] Depenni, R.[2022]

Citations

1. Austria pubmed.ncbi.nlm.nih.gov

Treatment of Advanced Metastatic Melanoma. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. [2023]

3. England pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. [2023]

9. England pubmed.ncbi.nlm.nih.gov

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF. [2023]

10. Italy pubmed.ncbi.nlm.nih.gov

[Long-term efficacy of encorafenib plus binimetinib combined treatment: case report.] [2021]

11. Italy pubmed.ncbi.nlm.nih.gov

[Treatment combinations in BRAF-mutant metastatic melanoma.] [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma. [2022]